Hxc3x6fle et al. describe the cytotoxic action of the natural substances epothilone A (R=hydrogen) and epothilone B (R=methyl) 
Epothilone A (R=H), Epothilone B (R=CH3) in, e.g., Angew. Chem. [Applied Chem.], 1996, 108, 1671-1673. Because of their in-vitro selectivity for breast cell lines and intestinal cell lines and their significantly higher activity against P-glycoprotein-forming, multiresistant tumor lines in comparison to taxol as well as their physical properties that are superior to those of taxol, e.g., a water solubility that is higher by a factor of 30, this novel structural class is especially advantageous for the development of a pharmaceutical agent for treating malignant tumors.
The natural substances are not sufficiently stable either chemically or metabolically for the development of pharmaceutical agents. To eliminate these drawbacks, modifications to the natural substance are necessary. Such modifications are possible only with a total-synthesis approach and require synthesis strategies that make possible a broad modification of the natural substance. The purpose of the structural changes is also to increase the therapeutic range. This can be done by improving the selectivity of the action and/or increasing the active strength and/or reducing undesirable toxic side-effects, as they are described in Proc. Natl. Acad. Sci. USA 1998, 95, 9642-9647.
The total synthesis of epothilone A is described by Schinzer et al. in Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew. Chem. 1997, 109, No. 5, pp. 543-544). Epothilone derivatives were already described by Hxc3x6fle et al. in WO 97/19086. These derivatives were produced starting from natural epothilone A or B. Also, epothilone C and D (double bond between carbon atoms 12 and 13: epothilone C=deoxyepothilone A; epothilone D=deoxyepothilone B) are described as possible starting products for this purpose.
Another synthesis of epothilone and epothilone derivatives was described by Nicolaou et al. in Angew. Chem. 1997, 109, No. 1/2, pp. 170-172. The synthesis of epothilone A and B and several epothilone analogs was described in Nature, Vol. 387, 1997, pp. 268-272; and the synthesis of epothilone A and its derivatives was described in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7960-7973 as well as the synthesis of epothilone A and B and several epothilone analogs in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7974-7991 also by Nicolaou et al.
Nicolaou et al. also describe in Angew. Chem. 1997, 109, No. 19, pp. 2181-2187 the production of epothilone A analogs using combinatory solid-phase synthesis. Several epothilone B analogs are also described there.
Epothilone derivatives, in some cases also epothilone C and D, are further described in Patent Applications WO 99/07692, WO 99/02514, WO 99/01124, WO 99/67252, WO 98/25929, WO 97/19086, WO 98/38192, WO 99/22461 and WO 99/58534.
In the epothilone derivatives that became known previously, no halogen atom can stand at carbon atom 16 of the epothilone skeleton.
The content of the priority documents DE 199 08 765.2 and DE 199 54 230.9 in this patent applicant as well as in WO 99/07692 of the applicant is incorporated by reference in these documents as part of the disclosure in this patent application.
The object of this invention consists in making available new epothilone derivatives, which are both chemically and metabolically stable enough for the development of pharmaceutical agents and which are superior to natural derivatives in terms of their therapeutic range, their selectivity of action and/or undesirable toxic side-effects and/or their active strength.
This invention describes the new epothilone derivatives of general formula I, 
in which
R1a, R1b are the same or different and mean hydrogen, C1-C10 alkyl, aryl, C7-C20 aralkyl, or together a xe2x80x94(CH2)m group with m=2, 3, 4 or 5,
R2a, R2b are the same or different and mean hydrogen, C1-C10 alkyl, aryl, C7-C20 aralkyl or together a xe2x80x94(CH2)n group with n=2, 3, 4 or 5,
R3 means hydrogen, C1-C10 alkyl, aryl, C7-C20 aralkyl,
G means an oxygen atom or a group CH2,
R4a, R4b are the same or different and mean hydrogen, C1-C10 alkyl, aryl, C7-C20 aralkyl or together a xe2x80x94(CH2)p group with p=2, 3, 4 or 5,
Dxe2x80x94E means a group 
R5 means hydrogen, C1-C10 alkyl, aryl, C7-C20 aralkyl, CO2H, CO2-alkyl, CH2OH, CH2O-alkyl, CH2O-acyl, CN, CH2NH2, CH2N(alkyl, acyl)1,2, CH2Hal
R6, R7 each mean a hydrogen atom, together an additional bond or an oxygen atom,
R8 means a halogen atom, or a cyano group,
X means an oxygen atom, two alkoxy groups OR23, a C2-C10 alkylene-xcex1,xcfx89-dioxy group, which can be straight-chain or branched, H/OR9 or a grouping CR10R11,
xe2x80x83whereby
R23 stands for a C1-C20 alkyl radical,
R9 stands for hydrogen or a protective group PGX,
R10, R11 are the same or different and stand for hydrogen, a C1-C20 alkyl, aryl, C7-C20 aralkyl radical
or R10 and R11 together with the methylene carbon atom together stand for a 5- to 7-membered carbocyclic ring,
Txe2x80x94Y means a group Oxe2x80x94C(xe2x95x90O), Oxe2x80x94CH2, CH2C(xe2x95x90O), NR24xe2x80x94C(xe2x95x90O), NR24xe2x80x94SO2,
R24 means hydrogen, C1-C10 alkyl,
Z means an oxygen atom or H/OR12,
xe2x80x83whereby
R12 is hydrogen or a protective group PGZ.
Halogen atom R8 can be a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine and bromine are preferred, and of the latter especially fluorine and chlorine.
R2a is preferably to mean a methyl, ethyl, propyl or butyl group.
A trimethylene group preferably commonly stands for substituents R1a and R1b, or R1a and R1b each mean a methyl group.
R10/R11 in group X preferably stand for a 2-pyridyl radical/hydrogen or a 2-methyl-4-thiazolyl radical/hydrogen or a 2-hydroxymethyl-4-thiazolyl radical/hydrogen or a 2-methyl-4-oxazolyl radical/hydrogen or a 2-hydroxymethyl-4-oxazolyl radical/hydrogen.
Txe2x80x94Y is preferably a group Oxe2x80x94C(xe2x95x90O) or a group NR24-C(xe2x95x90O).
Z primarily means an oxygen atom.
Between carbon atoms 10 and 11, there is a simple bond in the preferred compounds of general formula I, i.e., xe2x80x94Dxe2x80x94Exe2x80x94 stands for an ethylene group.
In addition, R3 usually stands for a hydrogen atom in the compounds according to the invention.
The combination H/CH3 preferably stands for the two substituents R4a/R4b.
An embodiment of the invention calls for those compounds of general formula I in which R8 stands for a fluorine atom or chlorine atom and R1a+R1b together mean a trimethylene group.
According to another embodiment, the invention relates to those compounds of general formula I in which R8 stands for a fluorine atom or chlorine atom and R10/R11 stand for a 2-pyridyl radical/hydrogen.
Still another variant are those compounds of general formula I in which R8 stands for a fluorine atom or chlorine atom, and R2a/R2b stand for ethyl/hydrogen.
Still another embodiment of the invention are those compounds of general formula I, in which R8 stands for a fluorine atom or chlorine atom, R1a+R1b together mean a trimethylene group and R2a/R2b stand for ethyl/hydrogen.
In addition, this variant for the compounds according to the invention can be mentioned in which R8 stands for a fluorine atom or chlorine atom, R2a/R2b stand for ethyl/hydrogen and R10/R11 stand for a 2-pyridyl radical/hydrogen.
Further embodiments of this invention will emerge from the features of the subclaims.
The production of the new epothilone derivatives is based on the linkage of three partial fragments A, B and C. This process is described in DE 197 51 200.3, date of application Nov. 13, 1997 as well as in the corresponding WO 99/07692 for the production of epothilone derivatives, which as R8 contain, for example, a methyl or longer alkyl group instead of the halogen atom according to the invention. The interfaces are as indicated in general formula Ixe2x80x2. 
A means a C1-C6 fragment (epothilone numbering system) of general formula 
in which
R1axe2x80x2, R1bxe2x80x2, R2axe2x80x2and R2bxe2x80x2 have the meanings already mentioned for R1a, R1b, R2a and R2b, and
R13 means CH2OR13a, CH2xe2x80x94Hal, CHO, CO2R13b, COHal,
R14 means hydrogen, OR14a, Hal, OSO2R14b,
R13a, R14a means hydrogen, SO2-alkyl, SO2-aryl, SO2-aralkyl or together a xe2x80x94(CH2)o group or together a CR15aR15b group,
R13b, R14b mean hydrogen, C1-C20 alkyl, aryl, C7-C20 aralkyl,
R15a, R15b are the same or different and mean hydrogen, C1-C10 alkyl, aryl, C7-C20 aralkyl or together a xe2x80x94(CH2)q group,
Hal means halogen (F, Cl, Br, I),
o means 2 to 4,
q means 3 to 6,
including all stereoisomers as well as their mixtures, and free hydroxyl groups in R13 and R14 can be etherified or esterified, free carbonyl groups can be ketalized in A and R13, converted into an enol ether or reduced, and free acid groups in A can be converted into their salts with bases.
B stands for a C7-C12 fragment (epothilone numbering system) of general formula 
in which
R3xe2x80x2, R4axe2x80x2, R4bxe2x80x2 and R5xe2x80x2 have the meanings already mentioned for R3, R4a, R4b and R5, and
D, E and G have the meanings that are indicated in general formula I, and
V means an oxygen atom, two alkoxy groups OR17, a C2-C10 alkylene-xcex1,xcfx89-dioxy group, which can be straight-chain or branched or H/OR16,
W means an oxygen atom, two alkoxy groups OR19, a C2-C10 alkylene-xcex1,xcfx89-dioxy group, which can be straight-chain or branched or H/OR18,
R16, R18, independently of one another, mean hydrogen or a protective group PG1 
R17, R19, independently of one another, mean C1-C20 alkyl.
C stands for a C13-C16 fragment (epothilone numbering system) of general formula 
xe2x80x83in which
R8xe2x80x2 has the meaning already mentioned in general formula I for R8 (halogen), and
R7xe2x80x2 means a hydrogen atom,
Txe2x80x2 means a group OR20, whereby R20 is a hydrogen atom or a protective group PG2, a halogen atom, preferably a bromine or iodine atom, an azido group or a protected amino group,
R21 means a hydroxy group, halogen, a protected hydroxy group OPG3, a phosphonium halide radical PPh3+Halxe2x88x92 (Ph=phenyl; Hal=F, Cl, Br, I), a phosphonate radical P(O) (OQ)2 (Q=C1-C10 alkyl or phenyl) or a phosphine oxide radical P(O)Ph2 (Ph=phenyl),
U means an oxygen atom, two alkoxy groups OR23, a C2-C10 alkylene-xcex1,xcfx89-dioxy group, which can be straight-chain or branched, H/OR9 or a grouping CR10R11,
xe2x80x83whereby
R23 stands for a C1-C20 alkyl radical,
R9 stands for hydrogen or a protective group PG3,
R10, R11 are the same or different and stand for hydrogen, a C1-C20 alkyl, aryl, C7-C20 aralkyl radical or R10 and R11 together with the methylene carbon atom commonly stand for a 5- to 7-membered carbocyclic ring.
As alkyl groups R1a, R1b, R2a, R2b, R3, R4, R5, R9, R10, R11, R12, R13b, R14b, R15a, R15b, R17 and R23, straight-chain or branched-chain alkyl groups with 1-20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
Alkyl groups R1a, R1b, R2a, R2b, R3, R4, R5, R9, R10, R11, R12, R13b, R14b, R15a, R15b, R17 and R23 can be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C1-C4 alkoxy groups, C6-C12 aryl groups (which can be substituted by 1-3 halogen atoms).
As aryl radicals R1a, R1b, R2a, R2b, R3, R4, R5, R9, R10, R11, R12, R13b, R14b, R15a and R15b, substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as, e.g., phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, CO2H, CO2-alkyl, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94N3, xe2x80x94CN, C1-C20 alkyl, C1-C20 acyl, C1-C20 acyloxy groups, are suitable. Heteroatoms in the heteroaryl radicals can be oxidized; thus, for example, the thiazole ring can be present in the form of N-oxide.
Unless otherwise indicated, the definition of xe2x80x9carylxe2x80x9d always also includes xe2x80x9cheteroaryl.xe2x80x9d
The aralkyl groups in R1a, R1b, R2a, R2b, R3, R4, R5, R9, R10, R11, R12, R13b, R14b, R15a and R15b can contain in the ring up to 14 C atoms, preferably 6 to 10, and in the alkyl chain 1 to 8, preferably 1 to 4 atoms. As aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are suitable. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO2H, CO2-alkyl, xe2x80x94NO2, xe2x80x94N3, xe2x80x94CN, C1-C20 alkyl, C1-C20 acyl, C1-C20 acyloxy groups.
The alkoxy groups that are contained in X in general formula I are in each case to contain 1 to 20 carbon atoms, whereby methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred.
As representatives of protective groups PG, alkyl- and/or aryl-substituted silyl, C1-C20 alkyl, C4-C7 cycloalkyl, which in addition in the ring can contain an oxygen atom, aryl, C7-C20 aralkyl, C1-C20 acyl and aroyl can be mentioned.
As alkyl, silyl and acyl radicals for protective groups PG, the radicals that are known to one skilled in the art are suitable. Preferred are alkyl or silyl radicals that can be easily cleaved from the corresponding alkyl and silyl ethers, such as, for example, the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical as well as alkylsulfonyl and arylsulfonyl radicals. As acyl radicals, e.g., formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino groups and/or hydroxy groups, are suitable.
Acyl groups PGX or PGZ in R9 and R12 can contain 1 to 20 carbon atoms, whereby formyl, acetyl, propionyl, isopropionyl and pivalyl groups are preferred.
As amino protective groups, the radicals that are known to one skilled in the art are suitable. For example, the Boc-, Z-, benzyl, f-Moc, Troc-, Stabase or Benzostabase groups can be mentioned.
Index m in the alkylene group that is formed from R1a and R1b preferably stands for 2, 3 or 4.
The C2-C10 alkylene-xcex1,xcfx89-dioxy group that is possible for X is preferably an ethyleneketal or neopentylketal group.
This invention relates in particular to the following compounds:
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-1-aza-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,10,12,16-pentamethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-1-aza-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,10,12,16-pentamethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z)7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-7,9,13-trimethyl-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-10,12,16-trimethyl-8,8-(1,3-trimethylene)-4,17-dioxabicyclo[14.1.0]hepta-deca-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl-7-ethyl-16-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16-dimethyl-10-ethyl-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylene)-4,17-dioxabicyclo[14.1.0]hepta-decane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-1-aza-7,9,13-trimethyl-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-10,12,16-trimethyl-8,8-(1,3-trimethylene)-4-aza-17-oxabicyclo[14.1.0]hepta-deca-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl-7-ethyl-16-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-1-aza-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16-dimethyl-10-ethyl-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylene)-4-aza-17-oxabicyclo[14.1.0]hepta-decane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-7,9,13-trimethyl-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-10,12,16-trimethyl-8,8-(1,3-trimethylene)-4,17-dioxabicyclo[14.1.0]hepta-deca-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl-7-ethyl-16-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16-dimethyl-10-ethyl-3-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylene)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-1-aza-7,9,13-trimethyl-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-10,12,16-trimethyl-8,8-(1,3-trimethylene)-4-aza-17-oxabicyclo[14.1.0]hepta-deca-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl-7-ethyl-16-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-1-aza-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16-dimethyl-10-ethyl-3-(1-chloro-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylene)-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-7,9,13-trimethyl-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-pyridyl)ethenyl)-10,12,16-trimethyl-8,8-(1,3-trimethylene)-4,17-dioxabicyclo [14.1.0]hepta-deca-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl-7-ethyl-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16-dimethyl-10-ethyl-3-(1fluoro-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-4,17-dioxabicyclo[14.1.0]hepta-decane-5,9-dione
4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-7,9,13-trimethyl-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro-2-(2-pyridyl)ethenyl)-10,12,16-trimethyl-8,8-(1,3-trimethylene)-4-aza-17-oxabicyclo[14.1.0]hepta-deca-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl-7-ethyl-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16-dimethyl-10-ethyl-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-4-aza-17-oxabicyclo[14.1.0]hepta-decane-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-7,9,13-trimethyl-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-pyridyl)ethenyl)-10,12,16-trimethyl-8,8-(1,3-trimethylene)-4,17-dioxabicyclo[14.1.0]hepta-deca-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl-7-ethyl-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16-dimethyl-10-ethyl-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-4,17-dioxabicyclo[14.1.0]hepta-decane-5,9-dione
4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-7,9,13-trimethyl-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro-2-(2-pyridyl)ethenyl)-10,12,16-trimethyl-8,8-(1,3-trimethylene)-4-aza-17-oxabicyclo[14.1.0]hepta-deca-5,9-dione
(4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl-7-ethyl-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5-(1,3-trimethylene)cyclohexadec-13-ene-2,6-dione
(1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16-dimethyl-10-ethyl-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylene)-4-aza-17-oxabicyclo[14.1.0]hepta-decane-5,9-dione
Representation of Partial Fragments A and B:
The partial fragments (synthesis components) of general formulas A and B can be produced as described in DE 19751200.3 or the corresponding WO 99/07692.
Representation of Partial Fragments C:
The representation of the partial fragments of formula C according to the invention, in which R8xe2x80x2 means a fluorine atom, can be performed as is indicated in the following formula schemes within the production of the compounds of Examples 1 to 4 according to the invention.
By variation of the (hetero)aryl radical in the starting product in reaction step a) (in this case, this is the 2-methyl-4-thiazolyl radical), the correspondingly substituted components of formula C and ultimately compounds of formula I result.
The production of fragments of formula C, in which R8xe2x80x2 means a chlorine atom, is described within Example 5.
If R8xe2x80x2 represents a bromine atom, this is introduced analogously to a chlorine atom in fragments C.
From Phosphonium Salt 1j Analogously to DE 19751200.3
From Phosphonium Salt 1j Analogously to Example 1


In addition to the compounds of general formula I, this invention also relates to the new C13-C16 epothilone components of general formula C as intermediate products 
in which
R8xe2x80x2 has the meaning that is already mentioned in general formula I for R8, and
R7xe2x80x2 means a hydrogen atom,
Txe2x80x2 means a group OR20, whereby R20 is a hydrogen atom or a protective group PG2, halogen or an azido group or a protected amino group,
R21 means a hydroxy group, halogen, a protected hydroxy group OPG3, a phosphonium halide radical PPh3+Halxe2x88x92 (Ph=phenyl; Hal=F, Cl, Br, I), a phosphonate radical P(O)(OQ)2 (Q=C1-C10 alkyl or phenyl) or a phosphine oxide radical P(O)Ph2 (Ph=phenyl),
U means an oxygen atom, two alkoxy groups OR23, a C2-C10 alkylene-xcex1,xcfx89-dioxy group, which can be straight-chain or branched, H/OR9 or a grouping CR10R11,
xe2x80x83whereby
R23 stands for a C1-C20 alkyl radical,
R9 stands for hydrogen or a protective group PG3,
R10, R11 are the same or different and stand for hydrogen, a C1-C20 alkyl, aryl, C7-C20 aralkyl radical or
R10 and R11 together with the methylene carbon atom commonly stand for a 5- to 7-membered carbocyclic ring.
According to the invention, those compounds of general formula C are preferred, in which
R8xe2x80x2 stands for a fluorine, chlorine or bromine atom, and/or
U stands for an oxygen atom, and/or
the aryl radical that stands for R10 and/or R11 stands for a phenyl radical that is optionally substituted with 1 to 3 radicals, selected from the group of substituents halogen, free hydroxy group or protected hydroxy group OPG5, CO2H, CO2-alkyl, C1-C4 alkyl, azido, nitro, nitrile, amino (NH2), or for a 5- or 6-membered heteroaryl radical that is optionally substituted with 1 to 2 C1-C4 alkyl radicals, especially for a substituent that is selected from the group of 2-, 3-furanyl, 2-, 3-, 4-pyridinyl, 2-, 4-, 5-thiazolyl- and 2-, 4- and 5-imidazolyl radicals, which optionally is substituted by 1 or 2 C1-C4 alkyl radicals, and/or
PG2 and PG3 are selected from the group of substituents methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl,
benzyl, para-nitrobenzyl, para-methoxybenzyl, acetyl,
propionyl, butyryl and benzoyl radicals, in particular PG2 is a tert-butyldimethylsilyl, acetyl,
benzoyl, benzyl or tetrahydropyranyl radical.
As protective groups PG4 and PG5, all protective groups that are indicated above for PG2 and PG3 are suitable.
In addition, this invention relates to partial fragments of general formula BC 
in which R3, R4a, R4b, R5, R8, D, E, G, Txe2x80x2 and U have the already mentioned meanings, and PG14 represents a hydrogen atom or a protective group PG.
In addition, this invention relates to partial fragments of general formula ABC 
in which R1axe2x80x2, R1bxe2x80x2, R2axe2x80x2, R2bxe2x80x2, R3, R4axe2x80x2, R4bxe2x80x2, R5, R6, R7, R8, R13, R14, D, E, G, Txe2x80x2, U and Z have the already mentioned meanings.
The representation and cyclization is also carried out analogously to what is described in DE 19751200.3 or the corresponding WO 99/07692, whereby now fragment C as substituent R8xe2x80x2 exhibits in particular a fluorine, chlorine or bromine atom:
Partial Fragments of General Formula AB 
in which R1axe2x80x2, R1bxe2x80x2, R2axe2x80x2, R2bxe2x80x2, R3, R4axe2x80x2, R4bxe2x80x2, R5, R13, R14, D, E, G, V and Z have the meanings already mentioned, and PG14 represents a hydrogen atom or a protective group PG, are obtained from the previously described fragments A and B according to the process that is shown in Diagram 1. 
Step a (A+Bxe2x86x92AB):
Compound B, in which W has the meaning of an oxygen atom and optionally present additional carbonyl groups are protected, is alkylated with the enolate of a carbonyl compound of general formula A. The enolate is produced by action of strong bases, such as, e.g., lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures.
Partial Fragments of General Formula ABC 
in which R1axe2x80x2, R1bxe2x80x2, R2axe2x80x2, R2bxe2x80x2, R3, R4axe2x80x2, R4bxe2x80x2, R5, R6, R7, R8, R13, R14, D, E, G, Txe2x80x2, U and Z have the already mentioned meanings, are obtained from previously described fragments AB and C according to the process that is shown in Diagram 2. 
Step b (AB+Cxe2x86x92ABC):
Compound C, in which R21 has the meaning of a Wittig salt, and optionally present additional carbonyl groups are protected, is deprotonated by a suitable base, such as, e.g., n-butyllithium, lithium diisopropylamide, potassium tert-butanolate, sodium or lithium-hexamethyldisilazide and reacted with a compound AB, in which V has the meaning of an oxygen atom.
Step c (ABCxe2x86x921):
Compounds ABC, in which R13 represents a carboxylic acid CO2H, Txe2x80x2 stands for OR20, and R20 represents a hydrogen atom, are reacted according to the methods that are known to one skilled in the art for the formation of large macrolides to compounds of formula I, in which Txe2x80x94Y has the meaning of Oxe2x80x94C(xe2x95x90O). Preferred is the method that is described in xe2x80x9cReagents for organic Synthesis, Vol. 16, p. 353xe2x80x9d with use of 2,4,6-trichlorobenzoic acid chloride and suitable bases, such as, e.g., triethylamine, 4-dimethylaminopyridine, sodium hydride.
Step d (ABCxe2x86x921):
Compounds ABC, in which R13 represents a group CH2OH and R20 represents a hydrogen atom, can be reacted preferably with use of triphenylphosphine and azodiesters, such as, for example, azodicarboxylic acid diethyl ester, to form compounds of formula I, in which Txe2x80x94Y has the meaning of Oxe2x80x94CH2.
Compounds ABC, in which R13 represents a group CH2OSO2 alkyl or CH2OSO2 aryl or CH2OSO2 aralkyl and R20 represents a hydrogen atom, can be cyclized to compounds of formula I, in which Txe2x80x94Y has the meaning of Oxe2x80x94CH2, after deprotonation with suitable bases, such as, for example, sodium hydride, n-butyllithium, 4-dimethylaminopyridine, Hxc3xcnig base, alkylhexamethyldisilazanes.
As an alternative to the route above, partial fragments of general formula BC 
in which R3, R4a, R4b, R5, R8, D, E, Txe2x80x2 and U have the already mentioned meanings, and PG14 represents a hydrogen atom or a protective group PG, can be obtained from the above-described fragments B and C according to the process that is shown in diagram 3. 
To introduce a nitrogen group at C-15, the oxygen group can be converted directly (Cxe2x80x2xe2x80x3 or BCxe2x80x2xe2x80x3 with Txe2x80x2=Nf=azide or a protected amine) or via the intermediate step of a halogen atom into a nitrogen group as desired in step Cxe2x80x2 (fragment C with Txe2x80x2=OR20) or BCxe2x80x2 (fragment BC with Txe2x80x2=OR20) at position 15: 
If R20 represents a hydrogen, the hydroxyl group can be converted according to the processes that are known to one skilled in the art into a halogen atom, preferably a chlorine, bromine or iodine atom, which then is converted into a nitrogen group Nf, whereby Nf preferably represents an azide or a protected amine. As an alternative, the hydroxyl group at C-15 (R20 in the meaning of hydrogen) can be converted into a leaving group, preferably into an alkyl- or aralkyl-sulfonate and the latter can be substituted by a nitrogen nucleophile Nf.
Partial fragments of general formula ABC 
in which R1axe2x80x2, R1bxe2x80x2, R2axe2x80x2, R2bxe2x80x2, R3, R4axe2x80x2, R4bxe2x80x2, R5, R6, R7, R8, R13, R14, D, E, G, Txe2x80x2, U and Z have the already mentioned meanings, are obtained from the above-described fragments BC and A according to the process that is shown in Diagram 4. 
The introduction of the nitrogen group at C-15 can also take place in step ABC as already described for Cxe2x80x2xe2x80x3 or BCxe2x80x2xe2x80x3. The flexible functionalization of described components A, B, and C also ensures a linkage sequence that deviates from the above-described process and that leads to components ABC. These processes are listed in the following table:
According to these processes, components A, B and C, as indicated in Diagram 5, can be linked: 
Free hydroxyl groups in I, Ixe2x80x2, A, B, C, AB, ABC can be further functionally modified by etherification or esterification, free carbonyl groups by ketalization, enol ether formation or reduction.
This invention relates to all stereoisomers of the described and claimed compounds and also their mixtures.
The new compounds of formula I are valuable pharmaceutical agents. They interact with tubulin by stabilizing microtubuli that are formed and are thus able to influence the cell-splitting in a phase-specific manner. This relates mainly to quick-growing, neoplastic cells, whose growth is largely unaffected by intercellular regulating mechanisms. Active ingredients of this type are in principle suitable for treating malignant tumors. As applications, there can be mentioned, for example, the therapy of ovarian, stomach, colon, adeno-, breast, lung, head and neck carcinomas, malignant melanoma, acute lymphocytic and myelocytic leukemia. The compounds according to the invention are suitable owing to their properties basically for anti-angiogenesis therapy as well as for treatment of chronic inflammatory diseases, such as, for example, psoriasis or arthritis. To avoid uncontrolled proliferation of cells and for better compatibility of medical implants, they can basically be applied or introduced into the polymer materials that are used for this purpose. The compounds according to the invention can be used alone or to achieve additive or synergistic actions in combination with other principles and classes of substances that can be used in tumor therapy.
As examples, there can be mentioned the combination with
Platinum complexes, such as, e.g., cis-platinum, carboplatinum,
intercalating substances, e.g., from the class of anthracyclines, such as, e.g., doxorubicin or from the class of anthrapyrazoles, such as, e.g., Cl-941,
substances that interact with tubulin, e.g., from the class of vinca-alkaloids, such as, e.g., vincristine, vinblastine or from the class of taxanes, such as, e.g., taxol, taxotere or from the class of macrolides, such as, e.g., rhizoxin or other compounds, such as, e.g., colchicine, combretastatin A-4,
DNA topoisomerase inhibitors, such as, e.g., camptothecin, etoposide, topotecan, teniposide,
folate- or pyrimidine-antimetabolites, such as, e.g, lometrexol, gemcitubin,
DNA-alkylating compounds, such as, e.g., adozelesin, dystamycin A,
inhibitors of growth factors (e.g., of PDGF, EGF, TGFb, EGF), such as, e.g., somatostatin, suramin, bombesin antagonists,
inhibitors of protein tyrosine kinases or protein kinases A or C, such as, e.g., erbstatin, genistein, staurosporine, ilmofosine, 8-Cl-cAMP,
antihormones from the class of antigestagens, such as, e.g., mifepristone, onapristone or from the class of antiestrogens, such as, e.g., tamoxifen or from the class of antiandrogens, such as, e.g., cyproterone acetate,
metastases-inhibiting compounds, e.g., from the class of eicosanoids, such as, e.g., PGl2, PGE1, 6-oxo-PGE1 as well as their more stable derivatives (e.g., iloprost, cicaprost, misoprostol),
inhibitors of oncogenic RAS proteins, which influence the mitotic signal transduction, such as, for example, inhibitors of the farnesyl-protein-transferase,
natural or synthetically produced antibodies, which are directed against factors or their receptors, which promote tumor growth, such as, for example, the erbB2 antibody.
a) IC50 values [nM] for the growth inhibition of human MCF-7 breast- and multi-drug-resistant NCl/ADR carcinoma cell lines of the epothilone derivatives with 13Z-olefins in a crystal-violet assay in comparison to epothilone D.
The compounds of Examples 1, 9, 13 and 17 have a significantly higher active strength in comparison to structurally similar reference compound epothilone D. Unlike in taxol, all compounds show an action on the multi-drug-resistant cell line NCl/ADR.
b) IC50 values [nM] for the growth inhibition of human MCF-7 breast- and multidrug-resistant NCl/ADR carcinoma cell lines of the epothilone derivatives with 13,14-xcex1-epoxide in a crystal-violet assay in comparison to epothilone B.
The compounds of Examples 3B, 14A, and 20A have a comparable or significantly higher active strength in comparison to structurally similar reference compound epothilone B. Unlike in taxol, all compounds show an action on the multi-drug-resistant cell line NCl/ADR. Compounds of Examples 3B and 10A show an improved selectivity in multi-drug-resistant cell line NCl/ADR in comparison to reference compound epothilone B.
The invention also relates to pharmaceutical agents that are based on pharmaceutically compatible compounds, i.e., compounds of general formula I that are nontoxic in the doses used, optionally together with commonly used adjuvants and vehicles.
According to methods of galenicals that are known in the art, the compounds according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local administration. They can be administered in the form of tablets, coated tablets, gel capsules, granulates, suppositories, implants, injectable, sterile, aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.
In this case, the active ingredient or ingredients can be mixed with the adjuvants that are commonly used in galenicals, such as, e.g., gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as Tweens or Myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, cleaning agents, dispersing agents, emulsifiers, preservatives and flavoring substances for taste correction (e.g., ethereal oils).
The compounds-according to the invention can be present in the form of xcex1-, xcex2- or xcex3-cyclodextrin clathrates or can be encapsulated in liposomes.
The invention thus also relates to pharmaceutical compositions that as active ingredients contain at least one compound according to the invention. A dosage unit contains about 0.1-100 mg of active ingredient(s). In humans, the dosage of the compounds according to the invention is approximately 0.1-1000 mg per day.
The examples below are used for a more detailed explanation of the invention, without intending that it be limited to these examples.